The present invention relates to a chemical process for the manufacture of fexofenadine or a pharmaceutically acceptable salt thereof, and to the manufacture of certain intermediates needed in said process. Fexofenadine is a compound of formula I

Fexofenadine is an antihistamine pharmaceutical drug for the treatment of allergy symptoms and it is a bronchodilator (U.S. Pat. No. 4,254,129, Richardson-Merrell Inc.).
The general synthesis known for fexofenadine via compounds of formula II and their conversion into fexofenadine is shown in scheme A below. A halogen compound of formula III is alkylated by the compound of formula IV, which is also designated as azacyclonol (U.S. Pat. No. 2,804,422, Merrel), to yield a keto compound of formula II, followed by reduction of the ketone and introduction of the propionic acid functionality either by saponification/hydrolysis (R1=carboxylic ester, amide, nitrile) or introduction of the carbonyl group by oxidation (R1=CH2OR2, R2 is acetyl, benzoyl or hydrogen) or by carbonylation (R1=H), yielding fexofenadine of formula I. The conversion of cyclopropyl aryl ketones V to the required gamma-halo ketones III with acids or Lewis-acids is also described in the literature.

The strategy for using III is described in U.S. Pat. No. 6,340,761 (Merrel), in scheme L and by the examples 43 to 60, where X is chloro and R1 is an ester or an amide functionality. The preparation of a gamma-halo ketone compound of formula III (X is chloro, R1 is COOEt) from the corresponding cyclic precursor V with dry hydrogen chloride is described in column 49, Example 12. The compound of formula V is described and used as one source for making a compound of formula III (e.g. schemes H or I), wherein R1 is a carboxylic acid or a carboxylic acid ester.
A similar compound of formula III (with X=iodide and R1=nitrile) is reported in WO 2002/010115 A1 (Texcontor) where its preparation from the cyclopropyl precursor with trimethylsilyl iodide is described (page 6, example 9).
This approach is also described by Wang et al. (Org. Proc. Res. and Dev. 2010, 14, 1464-68) wherein a compound of formula III (R1 is nitrile) is described and a detailed investigation of its reaction was done with various leaving groups X (X=chloro, bromo or tosylate) with yields of about 30 to 60% under varying conditions (Table 2 in Wang et al., reaction of compounds 6a-d with 7 to form 8 but also 8a). In competition to the desired alkylation compound V is formed as a side product. Product V obtained as side product (compound 8a in Wang et. al) explains the low yield, as it does not react anymore under these reaction conditions for the alkylation of III with IV (Scheme B). This side product V is the result of a cyclisation reaction of compound III which simultaneously competes with the desired bimolecular substitution reaction of III with IV. This cyclisation reaction is independent of the presence and concentration of azacyclonol IV and occurs as a intramolecular ketone alkylation within III which is facile even with weak bases such as NaHCO3 or Et3N as used in Table 2. These reactions are known as being very rapid with reaction rates too fast to be measured easily.

Under the reaction conditions described by Wang compound V is a dead-end product, which does not react further with compound IV and is thus not forming compound II. That indeed a further reaction of V with IV does not take place has been confirmed by the inventors by reacting compound IV with a compound of formula V, wherein R1 is CN, under the various reaction conditions described in Table 2 of Wang et al. (see Reference Example 1 below). Within the limit of detection (<0.1%) no formation of II from V was observed.
Thus, the gamma-halogen compounds of formula III obtained by the cyclopropyl opening of V and subsequently reacted with azacyclonol as shown in scheme A all have the disadvantages described for schemes A and B, namely the facile reverse reaction reforming the dead-end cyclopropyl ketone V by intramolecular ketone alkylation. In addition to the often low yield in the alkylation step the synthesis described for the compounds of formula III involve either long chemical sequences (4-5 steps) which use hazardous, highly toxic and expensive reagents or suffer from low yields and unselective chemical transformations.
Although it would be advantageous only few references deal with the idea of a direct reaction of a compound of formula V with IV in order to obtain a compound of formula II. WO 95/00482 (Albany Mol. Research) or equivalent U.S. Pat. No. 5,750,703 describe the use of substantially pure regioisomers of a compound of formula V (R1 is COOH or COOEt) to make a compound of formula III (X is chloro or iodo) and further a compound of formula II. Moreover, on page 29 and on page 30, lines 1-14 the reaction of these pure regioisomers of V with azacyclonol is described in general terms to be “carried out in a suitable solvent preferably in the presence of a base and optionally in the presence of a Lewis Acid such as magnesium, caesium, or calcium salts or trimethylsilyl chloride or in the presence of a catalytic amount of potassium iodide for about 4 to 120 hours at a temperature . . . ” (page 30, lines 1ff.). However, no example is given for this conversion. Indeed, implied in this description is again the synthetically equivalent opening of the cyclopropyl ketone V with the nucleophilic halide under acidic conditions such as the use of TMSCl alone or in the presence of a Lewis acid and possibly potassium iodide, followed by the coupling of the resulting compound III under basic conditions as described by e.g. Huang. Accordingly, it is not apparent for a person skilled in the art, which reaction conditions, if any, are to be chosen which would allow a direct conversion of the acid or ester precursor V to obtain compound II.
WO 03/000658 (Aurobindo Pharma) also claims the conversion of a compound designated formula I
with azacyclonol into II under so called “conditions effective to form the piperidine derivative compound” designated therein as XI (page 5). However, in practice (Example 7) the conditions are again those which first convert the cyclopropyl compound I into a compound of formula III as shown in Schema A (R1 is COOH) which in the subsequent step is coupled with azacyclonol.
WO2006/034092 (AMR technologies) describes the synthesis of fexofenadine in various ways. In scheme 4 (page 26) the reaction of a compound 10 (corresponding to the compound of formula V wherein R1 is COOMe) with azacyclonol is shown wherein the reaction is described to be done in the presence of TsOH. In scheme 3 the publication by Yovell et al. (J. Org. Chem. 42, 850-855, 1977) is referenced for these reaction conditions. However, the reaction was not performed (indicated by broken arrow—see para. 0046/page 20 for explanation; no example given). The cited reference of Yovell et al. itself investigates direct coupling of certain cyclopropyl ketones with secondary amines, such as piperidine (Table I) wherein the reaction is catalyzed by para-toluenesulfonic acid (p-TsOH). The reaction is occurring with overall moderate yield (30-65%) for the three amines used even though both the cyclopropyl ketone and the amines are simple structures compared to azacyclonol IV which contains in addition to the piperidine structure a highly hindered tertiary alcohol which is prone to the elimination of water by an SN1 type mechanism.
Indeed, performing the reaction under the conditions used by Yovell et al. (see Reference Example 2a below) leads to a slow conversion of IV and compound of formula V (R1 is CN) to give II. Using 10 mol % of pTsOH in xylene gave about 50% conversion after 20 hours at reflux. Attempts to increase the rate of the reaction by increasing the amount of catalyst to 1 equiv. of pTsOH resulted in a complete and rapid elimination of water from IV (see Reference Example 2b below). Thus, the rate of conversion and the formation of several impurities demonstrate that the acidic coupling conditions mentioned in WO2006/034092 are actually not suitable for a commercial preparation of II and by inference Fexofenadine.
Few other references describe the direct reaction of certain cyclopropyl aryl ketones being structurally different from V with simple amines to yield the gamma-amino ketones. First reported by Pocar et al. (Tetrahedron 1975, 31, 2427) gamma-amino ketones were obtained in low yield (<20%) from cyclopropyl aryl ketones and secondary amines by titanium tetrachloride catalysis. Using the same catalyst Boger et al. reported 28% yield of a gamma-amino ketone (J. Med. Chem. 2007, 50, 3359). Shi et al. reported the conversion of cyclopropyl aryl ketones with sulphonamides using stoichiometric amounts of Lewis acid catalyst Zr(OTf)4 (Synlett 2004, 1622). All the procedures published are without practical utility for the present problem as they suffer from low yields and expensive catalysts.
WO2007/135693 (IND-SWIFT Laboratories) describes the synthesis of fexofenadine (I) by direct coupling of an appropriately chosen derivative of a compound of formula V where the missing reactivity of V in the coupling with azacyclonol is overcome by the addition of a strongly polarizing and activating ester group on the cyclopropyl ketone by using a compound of formula VI
wherein R1 is COOalkyl. The activation is then enabling the direct reaction with azacyclonol to obtain a compound of formula VIII,
which has not been possible without this activation as described above.
In the example bridging pages 17 and 18 the reaction is described by reacting the ethyl ester with azacyclonol in DMSO at 60-65 degrees Celsius for 48 hours under nitrogen atmosphere. After work up 640 g of the ethylester of a compound of formula VIII was obtained, which, when calculated, corresponds to a yield of about 44%. This low yield is highlighting the challenge of directly opening a cyclopropyl ketone with an amine, even when the cyclopropyl ketone is additionally activated by an ethoxycarbonyl group. In addition to the moderate coupling yield forming VIII, the preparation of VI requires several additional steps and makes this approach less attractive.
In summary, the approach for preparing Fexofenadine by direct coupling of a compound of formula V with azacyclonol is not described in the art in a suitable manner as outlined above. The prior art does not describe or suggest suitable experimental conditions other than use of an acid described above by AMR Technology for coupling V (R1 is COOMe) or using an activated ester derivative of V (R1 is COOEt), both with limited success.